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Like many psychiatric drugs, antidepressants were discovered by accident. The first useful antidepressant group, Monoamine Oxidase Inhibitors (MAOI) were discovered in the early 1950's, and were originally developed to treat tuberculosis. The next group were the Tricyclic antidepressants. They were effective and safer than the MAOIs but still quite dangerous in overdose. They are still used today but have been largely replaced by Selective Serotonin Reuptake Inhibitors (SSRI). The first SSRI was fluoxetine (Prozac).

The three main classes of antidepressants have similar abilities to improve depressed mood, but the newer types are generally considered to have less severe side-effects and be less risky if taken in overdose.File:Antidepressants1.jpg

Selective serotonin reuptake inhibitorss (SSRIs) specifically prevent the reuptake of serotonin (increasing the level of serotonin in the synapses of the brain).

Monoamine oxidase inhibitors (MAOIs) block the destruction of neurotransmitters by enzymes which normally break them down.

Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and dopamine.

Although these drugs are effective in treating depression, exactly how they do it and why is not well understood. Curiously, when a person begins taking antipdepressants, the level in their blood increases to optimal levels in only a few days and begins affecting neurotransmitter activity immediately. Changes in mood, however, often take four weeks or more to appear.

It is risky to take antidepressants without a prescription. The selection of an antidepressant and the dosage suitable for a certain case and a certain person is a lengthy and complicated process, requiring the knowledge of a professional. Certain antidepressants can initially make depression worse, can induce anxiety, or can make a patient aggressive, dysphoric or acutely suicidal. In certain cases, an antidepressant can induce a switch from depression to mania or hypomania, can accelerate and shorten a manic cycle (i.e. promote a rapid-cycling pattern), or can induce the development of psychosis (or just the re-activation of latent psychosis) in a patient with depression who wasn't psychotic before the antidepressant.
Additionally, MAO inhibitors can produce a lethal hypertensive reaction if taken with foods that contain high levels of tyramine, such as cheese and wine. Likewise, lethal reactions to both prescription and over the counter medications have occurred. While more recent antipdepressant groups are considered safer, ongoing monitoring by a physician is essential.

Antidepressants can often cause side effects, and an inability to tolerate these is the most common cause of discontinuing the medication.

Although recent drugs may have fewer or less severe side effects, patients sometimes report severe side effects associated with their discontinuation, particularly with paroxetine. Additionally, a certain percentage of patients do not respond to certain antidepressant drugs, and require more than one attempt to find a suitable medication.

Antidepressants often make the manic component of bipolar disorder worse, and should be used with great care in the treatment of that disorder, usually in conjunction with a mood stabilisers.

Antidepressants do not seem to have all of the same addictive qualities as other substances such as nicotine, caffeine, cocaine, or other stimulants. There is, however, ongoing controversy on the definition of addiction. While some antidepressants may cause dependence and withdrawal they do not seem to cause uncontrollable urges to increase the dose due to euphoria or pleasure. For example, if an SSRI medication is suddenly discontinued, it may produce both somatic and psychological withdrawal symptoms, a phenomenon known as "SSRI discontinuation syndrome" (Tamam & Ozpoyraz, 2002). When the decision is made to stop taking antidepressants it is common practice to “wean” off of them by slowly decreasing the dose over a period of several weeks.

It has been noted that the most dangerous period for suicide in a patient with depression is immediately after treatment has commenced. Antidepressants reduce the symptoms of depression such as psychomotor retardation or lack of motivation before the mood starts to improve, heightening the person's physical well-being before their mental well-being similarly improves.

Although this appears to be a paradox, studies indicate the suicidal ideation is a relatively common component of the initial phases of antidepressant therapy, and it may be even more prevalent in younger patients such as pre-adolescents and teenagers.

It is strongly recommended that other family members and loved ones monitor the young patient's behavior, especially in the first eight weeks of therapy, for any signs of suicidal ideation or behaviors.

Sexual dysfunction is a very common side effect, especially with SSRIs. Bupropion, a NDRI, in many cases results in a moderately increased libido. Some clinicians have found that adding bupropion to a regimen of SSRI medications can sometimes alleviate some degree of sexual dysfunction. However, the mechanism of action for bupropion appears to be unique and quite different from other mood elevators, among these being a stimulant-like effect and concurrent insomnia, especially in the first few weeks of use. Moreover, some patients, as seen with most psycho-active drugs, cannot tolerate it at all.

Several studies have stimulated doubt about the effectiveness of antidepressants. The studies cite that the difference between antidepressants and a placebo is negligible. Antidepressants work only slightly better than placebo, and the Food and Drug Administration has not informed physicians of how little benefit most of these depression drugs offer (Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002a), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23[1]).

Through a Freedom of Information Act request, two psychologists obtained 47 studies used by the FDA for approval of the six antidepressants prescribed most widely between 1987-99. Overall, antidepressant pills worked 18 % better than placebos, a statistically significant difference, "but not meaningful for people in clinical settings," says University of Connecticut psychologist Irving Kirsch. He and co-author Thomas Moore released their findings in "Prevention and Treatment," an e-journal of the American Psychological Association.

More than half of the 47 studies found that patients on antidepressants improved no more than those on placebos, Kirsch says. "They should have told the American public about this. The drugs have been touted as much more effective than they are." He says studies finding no benefit have been mentioned only on labeling for Celexa, the most recently approved drug. The others included in his evaluation: Prozac, Paxil, Zoloft, Efexor and Serzone.

Additional papers have been published regarding the benefits of atypical vs. typical antidepresants. These are timely papers given the need for evidence based medicine, as well as the cost of health care. Discussion of a key paper reviewing this topic titled "Quantitative analysis of sponsorship bias in economic studies of antidepressants" can be found at an an on line journal club

Despite controversy, alternative treatments for depression such as the herbal remedy St John's wort and the amino acid derivative SAM-e have also gained popularity in recent years, although their effectiveness varies. Clinical trials have shown SAM-e to be as effective as standard antidepressant medication, with many fewer side effects (Delle Chiaie et al., 2002; Mischoulon and Fava, 2002). Most studies conclude that St. John's wort is usually as effective against depressions as other modern medication, again with fewer side effects, and it is widely prescribed for depression in Europe. However, a recent study showed St. John's wort to be no more effective than a placebo in cases of severe depression (Hypericum Depression Trial Study Group, 2002). Tryptophan dietary supplements, although banned in many countries due to impurities that caused a blood disease, have also been used as natural antidepressants. Dietary supplements of 5-HTP, a chemical the body forms from tryptophan and uses to make serotonin, have shown some promising research results but need further study.